Pharmacokinetics, -Dynamics and Safety of Intravenous Paracetamol in Neonates (PARANEO)

• ClinicalTrials.gov Identifier: NCT00969176
• Recruitment Status: Completed
• First Posted: September 1, 2009
• Last Update Posted: December 22, 2010
• Sponsor: Universitaire Ziekenhuizen Leuven
• Information provided by: Universitaire Ziekenhuizen Leuven

Study Description

Brief Summary:

The purpose of this study is triple, i.e. document single dose pharmacokinetics and -dynamics of intravenous paracetamol in preterm and term neonates after a loading dose (20 mg/kg iv bolus paracetamol), document multiple dose pharmacokinetics and -dynamics of intravenous paracetamol in preterm and term neonates, based on the daily doses routinely used within the neonatal intensive care unit and as reported in literature. Finally, document safety of single and repeated dose of intravenous paracetamol in preterm and term neonates.

Condition or disease	Intervention/treatment	Phase
Pain; Fever	Drug: paracetamol	Phase 2; Phase 3

Detailed Description:

Prospective, single center, open label study on the pharmacokinetics, -dynamics and safety of intravenous paracetamol in preterm and term neonates admitted in the neonatal intensive care unit, University Hospitals Leuven, Belgium. Patients will be included in this study after formal written informed consent of the parent(s). If a painful procedure is anticipated (e.g. surgery), parents should be informed preferably at least 24 h before the clinical indication will appear. Sixty neonates (i.e. < 29 days of postnatal age), either preterm (< 37 weeks gestational age) or term neonates will be included. At least 24 will be preterm neonates in order to ensure that the evaluated population reflects the typical population taken care for at the unit and in order to comply with the suggestions of EMEA (EMEA/CHMP/18922/05). The decision to prescribe paracetamol will be made by the attending neonatologist and in line with the current standing orders in the unit, i.e. either as a monotherapy for mild to moderate pain, independent of the cause (either postoperative, traumatic or medical) of pain or as part of multimodal analgesia for severe pain.

Before initiation of treatment and during any analgesic treatment, prospective evaluation of pain based on a validated and implemented pain scale (Leuven Neonatal Pain Scale, LNPS, Eur J Clin Pharmacol, 2003) is performed to further titrate treatment as needed. Additional administration or adaptation of any other analgesics as well as other concomitant medications will be recorded.

Paracetamol will be administered by either peripheral venous access or by deep venous catheter, ensuring that the study drug will always be administered alone and will be followed by an appropriate flush of normal saline, in line with the current guidelines at the unit. As soon as clinically feasible, the route of administration will be changed from intravenous to either oral (preferred) or rectal administration in line with the guidelines in the unit Plasma samples will be collected through an arterial line if present for clinical needs. In neonates without arterial access, plasma samples will only be collected when venipuncture is performed for clinical indications. The assessment of plasma pharmacokinetics will be based on a population pharmacokinetic approach in line with the EMEA guidelines on pharmacokinetic study in preterm and term neonates. The Leuven unit has published experience with such an approach (Eur J Clin Pharmacol, 2004) in the assessment of propacetamol pharmacokinetics.

Based on this population PK approach, we will focus on both early sampling (distribution volume, loading dose) and late sampling (clearance) while the total blood volume collected will not exceed 1.8 mL/kg for the complete study in line with the guidelines of EMEA on clinical research in children (EMEA website). It is a standing order at the unit that the procedural pain related to venous puncture is routinely treated with oral glucose (30 %).

When feasible, urine collections will be simultaneously performed (urinary bladder catheter in place for clinical indications, or by Uricol collection bag) in order to document aspects of paracetamol metabolism in neonates based on renal clearance in line with earlier studies reported on the assessment of paracetamol metabolism in early life (Acta Pediatric 2005). We anticipate urine collection in at least 20 neonates, of whom at least 8 preterm neonates.

We hereby have the intention to collect data on both pharmacokinetics, metabolism and pharmacodynamics of this drug in neonates.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 60 participants
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Single and Multiple Dose Trial to Evaluate Pharmacokinetics, -Dynamics and Safety of iv Paracetamol in Preterm and Term Neonates
• Study Start Date: September 2009
• Actual Primary Completion Date: December 2010
• Actual Study Completion Date: December 2010

Arms and Interventions

Arm	Intervention/treatment
No Intervention: paracetamol; not applicable, since all included cases will receive intravenous paracetamol	Drug: paracetamol; Intravenous paracetamol administration in neonates, loading dose 20 mg/kg, followed by a Gestational age-dependent maintenance dose of 10-20 mg/kg/24 h, divided in 4 doses (each 6h); Other Name: perfusalgan, perfalgan, paracetamol sintetica

Outcome Measures

Primary Outcome Measures :

1. Pharmacokinetics of intravenous paracetamol in neonates [ Time Frame: during administration of iv paracetamol and up to 24 hours after last administration ]

Secondary Outcome Measures :

1. Pharmacodynamics of intravenous paracetamol in neonates [ Time Frame: during administration of iv paracetamol and up to 6 hours after the last administration ]
2. Safety of intravenous paracetamol in neonates [ Time Frame: during and up to 48 h after last intravenous administration ]

Eligibility Criteria

• Ages Eligible for Study: up to 28 Days (Child)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Clinical indication of IV administration of paracetamol in neonates, as evaluated by the attending neonatologist

Exclusion Criteria:

• Recent administration of paracetamol (< 48 h) or clinical contra-indication for administration of paracetamol (hepatic failure).

Contacts and Locations

Locations

Belgium

University Hospitals Leuven

Leuven, Belgium, 3000

Sponsors and Collaborators

Universitaire Ziekenhuizen Leuven

Investigators

• Principal Investigator: karel allegaert, MD, PhD; Universitaire Ziekenhuizen Leuven

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Allegaert K, Naulaers G, Vanhaesebrouck S, Anderson BJ. The paracetamol concentration-effect relation in neonates. Paediatr Anaesth. 2013 Jan;23(1):45-50. doi: 10.1111/pan.12076. Epub 2012 Nov 21.

• Responsible Party: Allegaert Karel, University Hospitals Leuven, Belgium
• ClinicalTrials.gov Identifier: NCT00969176 History of Changes
• Other Study ID Numbers: S51597; EUdraCT nr 2009-011243-39
• First Posted: September 1, 2009
• Last Update Posted: December 22, 2010
• Last Verified: December 2010

Keywords provided by Universitaire Ziekenhuizen Leuven:

pain; fever; neonate; preterm; term; newborn

Additional relevant MeSH terms:

Fever; Body Temperature Changes; Signs and Symptoms; Acetaminophen; Analgesics, Non-Narcotic; Analgesics; Sensory System Agents; Peripheral Nervous System Agents; Physiological Effects of Drugs; Antipyretics